Reactive Oxygen Species (ROS) and Reproduction

  • Eve de Lamirande
  • Claude Gagnon
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 366)


The role of reactive oxygen species (ROS) in reproduction has long been the subject of investigation. As for other systems described in this book, there is compelling evidence for the involvement of ROS in physiology and pathology of both male and female reproductive systems. In this chapter, we will first briefly summarize informations linking ROS and the female reproductive functions, after which we will present in greater details the data in support for both the beneficial and detrimental effects of ROS on spermatozoa.


Reactive Oxygen Species Corpus Luteum Sperm Motility Follicular Fluid Seminal Plasma 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    C. Lyttle and E. DeSombre, Uterine peroxidase as a marker for estrogen action, Proc. Natl. Acad. Sci. USA 74:3162 (1977).PubMedCrossRefGoogle Scholar
  2. 2.
    Y. Lee, R. Howe S.-J. Sha, C. Teuscher, D. Sheehan and C. Lyttle, Estrogen regulation of an eosinophil chemotactic factor in the immature rat uterus, Endocrinology 125:3022 (1989).PubMedCrossRefGoogle Scholar
  3. 3.
    S. Klebanoff and D. Smith, Peroxidase-mediated antimicrobial activity of rat uterine fluid, Gynecol Invest 1:21 (1970).PubMedCrossRefGoogle Scholar
  4. 4.
    S. Klebanoff, Inactivation of estrogen by rat uterine preparations, Endocrinology 76:301 (1985).CrossRefGoogle Scholar
  5. 5.
    R Johri and P. Dasgupta, Hydrogen peroxide formation in the rat uterus under hormone-induced conditions, J. Endocrinol. 86:477 (1980).PubMedCrossRefGoogle Scholar
  6. 6.
    Y. Ishikawa, K. Hirai and K. Ogawa, Cytochemical localization of hydrogen peroxide production in the rat uterus, J. Histochem. Cytochem. 32:674 (1984).PubMedCrossRefGoogle Scholar
  7. 7.
    M.E. Hemler, H.W. Cook and W.E.M. Lands, Prostaglandin biosynthesis can be triggered by lipid peroxides, Arch. Biochem. Biophys. 193:340 (1979).PubMedCrossRefGoogle Scholar
  8. 8.
    J.D. Morrow, K.E. Hill, R.F. Burk, T.M. Nammour, K.F. Badr and L.J. Roberts, II. A series of prostaglandin F2-like compounds are produced in vivo in humans by a non-cyclooxygenase, free radical-catalyzed mechanism, Proc. Natl. Acad. Sci. USA 87:9383 (1990).PubMedCrossRefGoogle Scholar
  9. 9.
    P. Cherouny, R. Ghodgaonkar, J. Niebyl and N. Dubin, Effect of hydrogen peroxide on prostaglandin production and contractions of the pregnant rat uterus, Am. J. Obstet. Gynecol. 159:1390 (1988).PubMedGoogle Scholar
  10. 10.
    H. Minkoff, Prematurity: Infection as an etiologic factor, Obstet. Gynecol. 62:137 (1983).PubMedGoogle Scholar
  11. 11.
    L.L. Espey, Ovulation as an inflammatory reaction — A hypothesis, Biol. Reprod. 22:73 (1980).PubMedCrossRefGoogle Scholar
  12. 12.
    T. Miyazaki, K. Sueoka, A.M. Dharmarajan, S.J. Atlas, G.B. Bulkley and E.E. Wallach, Effect of inhibition of oxygen free radical on ovulation and progesterone production by the in-vitro perfused rabbit ovary. J. Reprod. Fertil. 91:207 (1991).PubMedCrossRefGoogle Scholar
  13. 13.
    H.R. Behrman, Prostaglandins in hypothalamo-pituitary and ovarian function, Annu. Rev. Physiol. 41:685 (1979).PubMedCrossRefGoogle Scholar
  14. 14.
    Y. Margolin, R. Aten and H. Behrman, Antigonadotropic and antisteroidogenic actions of peroxide in rat granulosa cells, Endocrinology 127:245 (1990).PubMedCrossRefGoogle Scholar
  15. 15.
    B.M. Shapiro, The control of oxidant stress at fertilization, Science 252:533 (1991).PubMedCrossRefGoogle Scholar
  16. 16.
    M.H. Nasr-Esfahani, J.R. Aitken and M.H. Johnson, Hydrogen peroxide levels in mouse oocytes and early cleavage stage embryos developed in vitro and in vivo, Development 109:501 (1990).PubMedGoogle Scholar
  17. 17.
    Y. Goto, Y. Noda, T. Mori and M. Nakano, Increased generation of reactive oxygen species in embryos cultured in vitro, Free Radic. Biol. Med. 15:69 (1993).PubMedCrossRefGoogle Scholar
  18. 18.
    Y. Noda, H. Matsumoto, Y. Umaoka, K. Tatsumi, J. Kishi and T. Mori, Involvement of superoxide radicals in the mouse two-cell block, Molec. Reprod. Develop. 28:356 (1991).CrossRefGoogle Scholar
  19. 19.
    Y. Goto, Y. Noda, K. Narimoto, Y. Umaoka and T. Mori, Oxidative stress on mouse embryo development in vitro, Free Radic. Biol. Med. 13:47 (1992).PubMedCrossRefGoogle Scholar
  20. 20.
    S. Natsuyma, Y. Noda, M. Yamashita, Y. Nagahama and T. Mori, Superoxide dismutase and thioredoxin restore defective p34cdc2 kinase activation in mouse two-cell block, Biochem. Biophys. Acta 176:90 (1993).Google Scholar
  21. 21.
    T. Tokura, Y. Noda, K. Narimoto, Y. Umaoka, T Mori and K Ogawa, Effect of superoxide dismutase on the developpement following the implantation stage in mice, Acta Histochem. Cytochem. 25: 491 (1992).CrossRefGoogle Scholar
  22. 22.
    M. Sawada and J.C. Carlson, Rapid plasma membrane changes in superoxide radical formation, fluidity and phospholipase A2 activity in the corpus luteum of the rat during induction of luteolysis, Endocrinology 128:2992 (1991).PubMedCrossRefGoogle Scholar
  23. 23.
    J.C. Carlson, X.M. Wu and M. Sawada, Oxygen radicals and the control of ovarian corpus luteum function, Free. Radic. Biol. Med. 14:79 (1993).PubMedCrossRefGoogle Scholar
  24. 24.
    J. C.M. Riley and H.R. Behrman, In vivo generation of hydrogen peroxide in the rat corpus luteum during luteolysis, Endocrinology 128:1749 (1991).PubMedCrossRefGoogle Scholar
  25. 25.
    J.R. Pepperell, K. Wolcott and H. R. Berhman, Effects of neutrophils in the rat luteal cells, Endocrinology 130: 1001 (1992).PubMedCrossRefGoogle Scholar
  26. 26.
    N. Sugino, Y. Nakamura, N. Okuno, M. Ishimatu, T. Teyama and H. Kato, Effects of ovarian ischemia-reperfusion on luteal function in pregnant rats, Biol. Reprod. 49: 345 (1993).CrossRefGoogle Scholar
  27. 27.
    X. Wu, K. Yao and J.C. Carlson, Plasma membrane changes in the rat corpus luteum induced by oxygen radical generation, Endocrinology 133: 491 (1993).PubMedCrossRefGoogle Scholar
  28. 28.
    H. Behrman and S. Preston, Luteolytic actions of peroxide in rat ovarian cells, Endocrinology 124:2895 (1989).PubMedCrossRefGoogle Scholar
  29. 29.
    H. Behrman and R. Aten, Evidence that hydrogen peroxide blocks hormonesensitive cholesterol transport into mitochondria of rat luteal cells, Endocrinology 128:2958 (1991).PubMedCrossRefGoogle Scholar
  30. 30.
    A. Sevanian, M.L. Wratten, L.L. McLeod and E. Kim, Lipid peroxidation and phospholipase A2 activity in liposomes composed of unsaturated phospholipids: A structural basis for enzyme activation, Biochem. Biophys. Acta 961:316 (1988).PubMedCrossRefGoogle Scholar
  31. 31.
    J. Halme, S. Becker and S. Haskill, Altered maturation and function of peritoneal macrophages: Possible role in pathogenesis of endometriosis, Am. J. Obstet. Gynecol. 156:783 (1987).PubMedGoogle Scholar
  32. 32.
    D.M. Portz, T.E. Elkins, R. White, J. Warren, S. Adadevoh and J. Randolph, Oxygen free radicals and pelvic adhesion formation: I. Blocking oxygen free radical toxicity to prevent adhesion formation in an endometriosis model, Int. J. Fertil. 36:39 (1991).PubMedGoogle Scholar
  33. 33.
    H. Koike, H. Egawa, T. Ohtsuka, M. Yamaguchi, T. Ikenoue and N. Mori, Eicosanoids production in endometriosis, Prostaglandins leukotrienes & essential fatty acids 45:313 (1992).CrossRefGoogle Scholar
  34. 34.
    E.R. Rosenblum, J.S. Gavaler and D.H. Van Thiel, Lipid peroxidation: A mechanism for alcohol-induced testicular injury, Free Radic. Biol. Med. 7:569 (1989).PubMedCrossRefGoogle Scholar
  35. 35.
    T. Nonogaki, Y. Noda, K. Narimoto, M. Shiotani, T. Mori, T. Matsuda and O. Yoshida, Localization of CuZn-superoxide dismutase in the human male genital organs, Human Reprod. 7:81 (1992).Google Scholar
  36. 36.
    R. Jones, T. Mann and R. Sherins, Peroxidative breakdown of phospholipids in human spermatozoa, spermicidal properties of fatty acid peroxides, and protective action of seminal plasma, Fertil Steril. 31:531 (1979).PubMedGoogle Scholar
  37. 37.
    R. Aitken and J. Clarkson, Cellular basis of defective sperm function and its association with the genesis of reactive oxygen species by human spermatozoa, J. Reprod. Fertil. 81: 459 (1987).PubMedCrossRefGoogle Scholar
  38. 38.
    J.G. Alvarez, J.C. Touchstone, L. Blasco and B.T. Storey, Spontaneous lipid peroxidation and production of hydrogen peroxide and superoxide in human spermatozoa. Superoxide dismutase as major enzyme protectant against oxygen toxicity, J. Androl. 8:338 (1987).PubMedGoogle Scholar
  39. 39.
    J.R. Aitken, J.S. Clarkson and S. Fishel, Generation of reactive oxygen species, lipid peroxidation and human sperm function, Biol Reprod. 40:183 (1989).CrossRefGoogle Scholar
  40. 40.
    J.G. Alvarez and B.T. Storey, Role of glutathione peroxidase in protecting mammalian spermatozoa from loss of motility caused by spontaneous lipid peroxidation, Gamete Res. 23:77 (1989).PubMedCrossRefGoogle Scholar
  41. 41.
    de Lamirande and C. Gagnon, Reactive oxygen species and human spermatozoa I. Effects on the motility of intact spermatozoa and on sperm axonemes, J. Androl. 13:368 (1992).PubMedGoogle Scholar
  42. 42.
    R.J. Aitken, D. Buckingham and D. Harkiss, Use of a xanthine oxidase free radical generating system to investigate the cytotoxic effects of reactive oxygen species on human spermatozoa, J. Reprod. Fert. 97:441 (1993).CrossRefGoogle Scholar
  43. 43.
    R.J. Aitken, D.S. Irvine and F.C. Wu, Prospective analysis of sperm-oocyte fusion and reactive oxygen species generation as criteria for the diagnosis of infertility, Am. J. Obstet. Gynecol 164:542Prospective analysis of sperm-oocyte fusion and reactive oxygen species generation as criteria for the diagnosis of infertility, Am. J. Obstet. Gynecol 164:542 (1991).Google Scholar
  44. 44.
    A. Iwasaki and C. Gagnon, Formation of reactive oxygen species in spermatozoa of infertile patients, Fertil. Steril. 57:409 (1992).PubMedGoogle Scholar
  45. 45.
    R.J. Aitken and K.M. West, Analysis of the relationship between reactive oxygen species production and leukocyte infiltration in fractions of human semen separated on Percoli gradients, Int. J. Androl. 13:433 (1990).PubMedCrossRefGoogle Scholar
  46. 46.
    R.J. Aitken, D. Buckingham, K. West, F.C. Wu, K. Zikopoulos and D.W. Richardson, Differential contribution of leucocytes and spermatozoa to the generation of reactive oxygen species in the ejaculates of Oligozoospermic patients and fertile donors, J. Reprod. Fert. 94:451 (1992).CrossRefGoogle Scholar
  47. 47.
    J.R. Aitken and J.S. Clarkson, Significance of reactive oxygen species and antioxidants in defining the efficacy of sperm preparation techniques, J. Androl. 9:367 (1988).PubMedGoogle Scholar
  48. 48.
    B. Rao, J.C. Soufir, M. Martin and G. David, Lipid peroxidation in human spermatozoa as related to midpiece abnormalities and motility, Gamete Res. 24: 127 (1989).PubMedCrossRefGoogle Scholar
  49. 49.
    R. D’Agata, E. Vicari, M.L. Moncada, G. Sidoti, A.E. Calogero, M.C. Fornito, G. Minacapilli, A. Mongioi and P. Polosa, Generation of reactive oxygen species in subgroups of infertile men, Int. J. Androl. 13:344 (1990).PubMedCrossRefGoogle Scholar
  50. 50.
    H.P. Nissen and H.W. Kreysel, Superoxide dismutase in human semen, Klin. Wochenschr. 61:63 (1983).PubMedCrossRefGoogle Scholar
  51. 51.
    C. Jeulin, J.C. Soufir, P. Weber, D. Laval-Martin and R. Calvayrac, Catalase activity in human spermatozoa and seminal plasma, Gamete Res. 24:185 (1989).PubMedCrossRefGoogle Scholar
  52. 52.
    J.G. Alvarez and B.T. Storey, Taurine, hypotaurine, epinephrine and albumin inhibit lipid peroxidation in rabbit spermatozoa and protect against loss of motility, Biol Reprod. 29:548 (1983).PubMedCrossRefGoogle Scholar
  53. 53.
    B. Halliwell and J.M.C. Gutteridge, “Free Radicals inBiology and Medicine”, 2nd edition, Clarendon Press, Oxford (1989).Google Scholar
  54. 54.
    E. de Lamirande and C. Gagnon, Reactive oxygen species and human spermatozoa II. Depletion of adenosine triphosphate plays an important role in the inhibition of sperm motility, J. Androl. 13:379 (1992).PubMedGoogle Scholar
  55. 55.
    C.K. Chow, Vitamin E and oxidative stress, Free Radic. Biol. Med. 11:215 (1991).PubMedCrossRefGoogle Scholar
  56. 56.
    E.B. Dawson, W.A. Harris, M.C. Teter and L.C. Powell, Effect of ascorbic acid supplementation on the sperm quality of smokers, Fertil. Steril. 58:1034 (1992).PubMedGoogle Scholar
  57. 57.
    T. Kobayashi, T. Miyazaki, M. Natori and S. Nozawa, Protective role of superoxide dismutase in human sperm motility: superoxide dismutase activity and lipid peroxide in human seminal plasma and spermatozoa, Human Reprod. 6:987 (1991).Google Scholar
  58. 58.
    A. Zini, E. de Lamirande and C. Gagnon, Reactive oxygen species in semen of infertile patients: levels of superoxide dismutase-and catalase-like activities in seminal plasma and spermatozoa, Int. J. Androl. 16:183 (1993).PubMedCrossRefGoogle Scholar
  59. 59.
    R.J. Aitken, D.W. Buckingham and K.M. West, Reactive oxygen species and human spermatozoa: analysis of the cellular mechanisms involved in luminol-and lucigenin-dependent chemiluminescence, J. Cell Physiol. 151:466 (1992).PubMedCrossRefGoogle Scholar
  60. 60.
    M. Gavella, V. Lipovac and T. Marotti, Effect of pentoxifylline on superoxide anion production by human sperm, Int. J. Androl. 14:320 (1991).PubMedCrossRefGoogle Scholar
  61. 61.
    M. Gavella and V. Lipovac, NADH-dependent oxidoreductase (diaphorase) activity and isozyme pattern of sperm in infertile men, Arch. Androl. 28:135 (1992).PubMedCrossRefGoogle Scholar
  62. 62.
    E. Kessopoulou, M.J. Tomlinson, C.L.R. Barratt, A.E. Bolton and I.D. Cooke, Origin of reactive oxygen species in human semen: spermatozoa or leucocytes? J. Reprod. Fert. 94:463 (1992).CrossRefGoogle Scholar
  63. 63.
    N.N. Kovalski, E. de Lamirande and C. Gagnon, Reactive oxygen species generated by human neutrophils inhibit sperm motility: protective effect of seminal plasma and scavengers, Fertil. Steril. 58:809 (1992).PubMedGoogle Scholar
  64. 64.
    E. de Lamirande, C.W. Bardin and C. Gagnon, Aprotinin and a seminal plasma factor inhibit the motility of demembranated reactivated rabbit spermatozoa, Biol. Reprod. 28:788 (1983).PubMedCrossRefGoogle Scholar
  65. 65.
    R. Yanagimachi, Mammalian fertilization, in: “The Physiology of Reproduction,” E. Knobil, J.D. Neil, L.L. Ewing, C.L. Markert, G.S. Greenwald and D.W. Pfaff, eds., Raven Press, New York (1988).Google Scholar
  66. 66.
    L.J. Burkman, Hyperactivated motility of human spermatozoa during in vitro capacitation and implications for fertility, in: “Controls of Sperm Motility,” C. Gagnon, ed., CRC Press, Boca Raton, FL (1990).Google Scholar
  67. 67.
    A.I. Yudin, W. Gottlieb and S. Meizel, Ultrastructural studies of the early events of the human sperm acrosome reaction as initiated by human follicular fluid, Gamete Res. 20:11 (1988).PubMedCrossRefGoogle Scholar
  68. 68.
    E. de Lamirande and C. Gagnon, A positive role for the superoxide anion in triggering hyperactivation and capacitation of human spermatozoa, Int. J. Androl. 16:21 (1993).PubMedCrossRefGoogle Scholar
  69. 69.
    E. de Lamirande and C. Gagnon, Human sperm hyperactivation and capacitation as parts of an oxidative process, Free Radic. Biol. Med. 14:157 (1993).PubMedCrossRefGoogle Scholar
  70. 70.
    I. Bize, G. Santander, P. Cabello, D. Driscoll and C. Sharpe, Hydrogen peroxide is involved in hamster sperm capacitation in vitro, Biol. Reprod. 44:398 (1991).PubMedCrossRefGoogle Scholar
  71. 71.
    E. de Lamirande, D. Eiley, and C. Gagnon, Inverse relationship between the induction of human sperm capacitation and spontaneous acrosome reaction by various biological fluids and the superoxide scavenging capacity of these fluids, Int. J. Androl. 16: 258 (1993).PubMedCrossRefGoogle Scholar
  72. 72.
    E. de Lamirande and C. Gagnon, Human sperm hyperactivation in whole semen and its association with low superoxide scavenging capacity in seminal plasma, Fertil. Steril. 59:1291 (1993).PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1994

Authors and Affiliations

  • Eve de Lamirande
    • 1
    • 2
  • Claude Gagnon
    • 1
    • 2
  1. 1.Urology Research LaboratoryRoyal Victoria HospitalCanada
  2. 2.Faculty of MedicineMcGill UniversityMontréalCanada

Personalised recommendations